Accumulation of ?-amyloid (A?) in the form of brain plaques is a hallmark of Alzheimer's disease (AD). Multiple studies in humans as well as mouse AD models have shown dystrophic neurites inside and surrounding A? plaques, and shown a slew of neuronal deficits correlated with A? deposition that likely contribute to memory loss and cognitive decline seen in AD. A? accumulation could be the result of excessive production or defective clearance of A?, or a combination of both. Many studies have focused on the production of pathogenic forms of A?, in particular A?42. Much less is known about the clearance process of A? from the brain. A strong indication that defective A? clearance is involved in the pathogenesis of AD comes from studies showing that the concentration of A?42 in the cerebrospinal fluid (CSF) is lower in AD patients relative to controls very early in the disease process. In preliminary studies, we have observed a rapid and efficient uptake of dextran rhodamine and A?42 by meningeal macrophages. By specifically ablating meningeal macrophages in the brain, we will test the hypothesis that meningeal macrophages are important in the clearance of A? and therefore their absence contributes to an incrased AD plaque size. We further hypothesize that meningeal macrophages do not work as effectively in AD as in healthy undividuals, as measured by number and/or phagocytic capacity and/or activation state. The proposed studies will elucidate important functions of meningeal macrophages in regulating amyloid clearance and deposition in the pathogenesis of AD.